Heretofore contrast agents for improving magnetic resonance imaging of protons have consisted of magnetizable substances comprising metals or metallic compounds. Such contrast agents may be paramagnetic, ferromagnetic, or superparamagnetic, and act through dipole interactions with tissue protons. Where the substance is toxic, such as gadolinium, it can be administered in chelated form. In another kind of MRI contrast agent, ultrafine particles of a ferromagnetic or superparamagnetic material, such as magnetite (Fe.sub.3 O.sub.4), have been dispersed in a biodegradable matrix material, and formed into microspheres which are capable of passing through capillaries. Such MRI contrast agents are described in U.S. Pat. Nos. 4,675,173 and 4,849,217. A preferred biodegradable material is human serum albumin. Albumin is not known to have any MRI contrast-producing properties. It is the magnetizable particles dispersed in the albumin which produces the MRI contrast effect.
It is known that gas microbubbles are strong scatterers of ultrasonic waves in fluid media, and may therefore be useful as an imaging agent for ultrasonic echographic imaging (U.S. Pat. No. 4,276,885). The preparation and use of microbubble ultrasonic imaging agents are described in U.S. Pat. Nos. 4,718,433, 4,572,203, 4,657,756 and 4,774,958. U.S. Pat. No. 4,657,756 suggests that microbubbles can alter the transmission characteristics of electromagnetic waves and therefore might have applications in "x-ray imaging (e.g., CT scanning), NMR imaging, microwave imaging, and marine sonar" (col. 3, lines 43-44). However, the patent contains no examples or other disclosure as to how such applications could be carried out.
Stabilized, concentrated gas-center microspheres in small enough diameters to pass through the capillaries are described in U.S. Pat. No. 4,844,882. A product of this kind designed for ultrasonic imaging use has been produced by Molecular Biosystems, Inc., of San Diego, Calif., and is known by the registered trademark "ALBUNEX". Another kind of gas-carrying ultrasonic imaging particles are described in published European Patent Application 0 365 467. Gas bubbles are carried by solid particles that are small enough to pass through the capillaries.
As far as is known no one has heretofore described a method for using microbubbles as an MRI contrast agent. MRI utilizes radio frequency pulses and magnetic field gradients applied to a subject in a strong field to produce the images. The scientific principles and mechanisms involved are entirely different from ultrasonic imaging which utilizes high frequency sound waves.
There is voluminous literature on magnetic resonance imaging, and a number of United States and foreign companies manufacture equipment for experimental and clinical MRI applications. Existing knowledge in the field of contrast agents for use in MRI was surveyed in a recent treatise entitled "Enhanced Magnetic Resonance Imaging", edited by Val M. Runge (1989, C. V. Mobsy Company); and see also Peter G. Morris, "Nuclear Magnetic Imaging in Medicine and Biology", (1986, Oxford University Press). Accepted MRI terminology includes the following definitions which are applicable to this application.